Z-5-Carboxymethylene-1,3-dioxolan-4-ones of formula A (where R1 and R2 can be independently H, alkyl or aryl) have been widely utilized as synthetic intermediates in Diels-Alder and free radical chemistry as well as in the preparation of HIV integrase inhibitors as disclosed in WO 2004/004657.
A process for preparing a compound of formula A (R1,R2=pentamethylene) is described by Ramage and McCleery in J. Chem. Soc. Perkin Trans. I, pages 1555-1560, 1984. This process utilizes a Wittig reaction between anhydrous tert-butyl glyoxylate and a heterocyclic phosphorane. However, this process is inefficient and not suitable for large scale manufacturing of compounds of formula A

An improved procedure for the synthesis of compounds of formula A (R1=tert-butyl, R2═H) from S-malic acid is reported by Kneer et. al. in Synthesis, pages 599-603, 1990. This procedure utilizes acetal-protected malic acid B as starting material. Because malic acid is not in the correct oxidation state for direct conversion to A, it is necessary to carry out a bromination reaction. However, bromination of the free carboxylic acid results in extensive decarboxylation so that it is necessary to first convert the acid to an ester and then hydrolyze the ester at the end of the synthetic sequence. This fact, coupled with the limited selectivity of the bromination reaction, limits the efficiency of the overall process.

In principle, the requirement for a bromination step would be circumvented by using a derivative of inexpensive tartaric acid as a starting material. Unlike malic acid, tartaric acid is already in the correct oxidation state to produce A via an elimination reaction. A suitable derivative for such a process would be the bis-ketal C. Preparation of such a compound was reported by Fischer and Taube in Chem. Ber., Vol. 60, pages 485-490, 1927, who prepared C(R1═R2=methyl) by the action of acetone on tartaric acid in the presence of either zinc chloride or hydrogen chloride. Subsequently an improved preparation of the same compound C was reported by Dermer and George in Proc. Oklahoma Acad. Sci. Vol. 52, pages 66-69, 1972, who utilized boron trifluoride as a catalyst. For the synthesis of bis-acetal derivatives (i.e., R1═H, R2=alkyl) Markert et. al. in Tetrahedron Asymm. Vol. 15, pages 803-806, 2004 report that lithium perchlorate is a superior catalyst.

Although there is no report of the conversion of C to A in the literature, elimination reactions on other systems are reported to proceed in the presence of very strong bases such as lithium diisopropylamide or sodium hydride. For example, Jarosz and Ciunik in Pol. J. Chem., Vol. 72, pages 1182-1190, 1998 used lithium diisopropylamide to effect such an elimination reaction on compound D while Ferezou et. al. in Bull. Soc. Chim. Fr., Vol. 131, pages 865-894, 1994 used sodium hydride to effect an elimination reaction on compound E. However, as will be shown in Example 3 below, neither lithium diisopropylamide nor sodium hydride is effective for the conversion of C to A. Thus, the discovery that nominally weaker potassium-containing bases allow the facile conversion of C to A is clearly unexpected even to one skilled in the art.
